Biology Reference
In-Depth Information
mannose and elevated cAMP (
Yin et al., 2003
). When isolated and analyzed
by mass spectrometry, the active component proved to be oncomodulin
(Ocm), a small calcium-binding protein that is unrelated to any of the
better-known trophic factors. When tested in culture in the presence of
mannose and forskolin (an activator of adenylate cyclase that leads to
elevated cAMP levels), Ocm induced considerably greater outgrowth
than factors such as BDNF, FGF2, CNTF, or GDNF, with an EC
50
of
2.8 nM (
Yin et al., 2006
). Conversely, immunodepletion of Ocm
eliminated the axon-promoting effects of macrophage-conditioned
media. Ocm exhibits high-affinity binding to a cell surface receptor on
RGCs. This binding is cAMP dependent and may reflect a role for
cAMP in causing the Ocm receptor to translocate from an intracellular
pool to the cell surface (
Yin et al., 2006
). Within a day after injecting
Zymosan, cells that infiltrate the eye show high levels of Ocm mRNA
and protein (
Yin et al., 2009
). The protein is secreted from these
infiltrative cells, crosses the inner limiting membrane, and binds heavily
to RGCs and their dendrites (
Kurimoto et al., 2010
). The specificity of
this binding is demonstrated by its displacement by a 22-aa peptide that
competes with Ocm for receptor occupancy, and by the loss of binding
using a cAMP antagonist, Rp-cAMP (
Kurimoto et al., 2010
).
Functionally, infusion of Ocm plus a cAMP analog from slow-release
polymeric beads mimics the effects of intraocular inflammation (
Fig. 6.1
;
Yin et al., 2006
), whereas conversely, the 22-aa blocking peptide or a
neutralizing antibody to Ocm strongly reduces inflammation-induced
axon regeneration (
Fig. 6.1
;
Yin et al., 2009
). Together, these data show
that Ocm plays a central role in mediating the effects of intraocular
inflammation on optic nerve regeneration (
Fig. 6.1
). However, other
factors appear to be involved as well. For one thing, Ocm binding and
activity require elevation of intracellular cAMP, which implies that a
separate factor associated with inflammation leads to elevation of cAMP
levels in RGCs. Second, although reagents that block Ocm from binding
to its receptor suppress the effects of inflammation on axon regeneration,
they do not alter the effects of inflammation in enhancing RGC survival
after optic nerve injury (
Kurimoto et al., 2010; Yin et al., 2009
). This
observation indicates the existence of one or more factors associated with
inflammation that promote RGC survival.
A distinction between factors mediating axon regeneration and cell sur-
vival is also seen in experiments showing that, whereas induction of an inflam-
matory response in either the posterior chamber of the eye or the cut end of
